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Neuroinflammation often is described as the underlying process responsible for toxicant-induced damage to the CNS. While glial activation and the attendant expression of proinflammatory mediators often are associated with CNS damage, it is not clear that a cause-and-effect relationship exists between the presence of a neuroinflammatory process and neural damage. We explored this issue with two models of dopaminergic neurotoxicity. We used single low-dose regimens of MPTP or METH to cause selective degeneration of striatal dopaminergic nerve terminals without affecting cell bodies in the nigra. Both compounds increased the expression of the microglia associated factors, F4/80, Il-1alpha, Il6, Ccl2 and Tnf-alpha and also elicited morphological evidence of microglial activation prior to induction of astrogliosis. Pharmacological antagonism of MPTP and METH neurotoxicity prevented these proinflammatory responses, findings suggestive of a link between neuroinflammation and the observed neurotoxic outcomes. Nevertheless, when minocycline was used to suppress the expression of all these mediators, with the exception of Tnf-alpha, we failed to see neuroprotection. Likewise, when we examined the effects of MPTP or METH in transgenic mice lacking Il6, Ccl2 or Tnfr1/2 genes, deficiency of either Il6 or Ccl2 did not alter neurotoxicity, whereas deficiency in Tnfr1/2 was neuroprotective. Although these observations pointed to a role of the proinflammatory cytokine, TNF-alpha, in the neurotoxic effects of MPTP and METH, other observations did not support this argument. For example, induction of iNOS or activation of NF-kappaB, effects linked to inflammatory responses and free radical formation, was not observed. Moreover, immunosuppressive regimens of glucocorticoids failed to suppress TNF-alpha, or block neurotoxicity. Taken together, our observations suggest that MPTP and METH neurotoxicity are associated with a "neuroinflammatory" response, yet this response lacks key features of inflammation and, with the exception of TNF-alpha, neurotoxicity appears to be the cause rather than the consequence of proinflammatory signals.